Colorectal cancer (CRC) is one of the most frequently occurring cancers in the U.S., with more than 140,000 new cases and about 50,000 deaths expected to occur in 2010. 5-fluorouracil (5-FU) based chemotherapy represents the gold standard for CRC treatment both in the adjuvant and metastatic setting. However, primary or acquired resistance to pyrimidine analog treatments represents a common problem in the management of CRC patients. These observations highlight the need for a better understanding of resistance mechanisms and more effective therapies.
MicroRNAs are a class of small non-coding RNAs that act as post-transcriptional regulators of gene expression and cell homeostasis. Over-expression of miR-21 is a common trait of many solid and hematological malignancies. miR-21 over-expression has been found in blood and stool samples from patients affected by CRC. Moreover, miR-21 over-expression is associated with poor benefit from 5-FU adjuvant chemotherapy in stage II and III CRC.
The Mismatch Repair (MMR) System is involved in DNA damage recognition and repair. hMSH2 and hMLH1 function as core MMR proteins and form heterodimers with protein homologs hMSH3 or hMSH6 and hMLH3 or hPMS2 respectively. Heterodimer formation is fundamental for the DNA damage recognition and represents a crucial step for the stability of the MMR protein homologs. Defects in MMR proteins have been associated with reduced or absent benefit from 5-FU adjuvant chemotherapy in clinical trials. MMR impairment appears to cause reduced incorporation of 5-FU metabolites into DNA leading to reduced G2/M arrest and apoptosis after 5-FU treatment.
The over-expression of miR-21 is linked to a number of human tumors including colorectal cancer, where it appears to regulate the expression of tumor suppressor genes including p21, PTEN, TGFβRII and Bax.